Human parathyroid hormone (hPTH) is an 84 amino acid protein that is secreted by the parathyroid gland; PTH is involved in calcium and phosphorus homeostasis and the control of bone growth and density. Two forms of recombinant hPTH have been evaluated in clinical trials, hPTH(1-34) and the full length 84-amino acid, hPTH(1-84). hPTH (1-34) is an N-terminal fragment of PTH, which, along with fragment 1-38, retains the full biological activity of the intact protein.
A recombinant, rDNA-derived, injectable form of hPTH(1-34) (teriparatide) was approved in the United States in 2002 for the treatment of severe osteoporosis and is sold under the tradename FORTEO® (Eli Lilly), referred to hereafter as subcutaneously injected teriparatide. The subcutaneously injected teriparatide is typically prescribed for women with a history of osteoporotic fracture, those having multiple risk factors for fracture, or who have failed or are intolerant of other osteoporosis therapies. In postmenopausal women, subcutaneously injected teriparatide has been found to increase bone mineral density and reduce the risk of vertebral and non-vertebral fractures. Subcutaneously injected teriparatide has also been described to increase bone mass in men with primary or hypogonadal osteoporosis who are at a high risk for fracture. In men with primary or hypogonadal osteoporosis, subcutaneously injected teriparatide has similarly been reported to increase bone mineral density. In 2009, subcutaneously injected teriparatide was also approved for treatment of osteoporosis in men and women associated with sustained systemic glucocorticoid therapy at high risk for fracture.
Bone degenerative diseases such as osteoporosis occur in a substantial portion of the senior adult population. Osteoporosis encompasses a heterogeneous group of disorders that represent a major risk for bone fractures, and a substantial burden on the health care system. Billions of dollars are spent annually on medical care for the treatment of osteoporosis. Clinically, osteoporosis is characterized by diminished bone mass, decreased bone mineral density (BMD) and bone mineral content (BMC), and loss of bone architecture resulting in decreased bone strength and increased risk of bone fracture.
While a number of antiresorptive agents including calcitonin, bisphosphonates, estrogen, and selective estrogen receptor modulators (SERMs) prevent further bone loss, they do not rebuild bone once it has been lost. This is in contrast to subcutaneously injected teriparatide, which represents the first-FDA approved anabolic bone building agent for the treatment of osteoporosis. PTH or PTH(1-34) is thought to exert its effects through receptor-mediated activation of two intracellular signaling pathways via (1) adenylate cyclase and protein kinase A, and (2) phospholipase C and protein kinase C. PTH(1-34) builds bone mass, restores bone architecture, and reduces the risk of vertebral and non-vertebral bone fractures in osteoporotic patients who are at high risk of fracture (R. Neer, NEJM, 344:1434, 2001).
As a peptide product, PTH(1-34) requires daily subcutaneous injections an administration regime that is less than ideal. Indeed, most patients have an aversion to self-injection of drugs, and the need to visit a clinic or doctor's office for administration is inconvenient and burdensome. Moreover, severely osteoporotic patients may be unable to self-administer such injections, such that each of the foregoing factors can contribute to poor patient compliance.
While other forms of administration have been suggested, such as oral delivery to the stomach, transdermal delivery, and nasopharyngeal absorption, none of these delivery routes has been proven to be particularly effective and each suffers from certain drawbacks. Oral delivery results in very low bioavailability of polypeptide drugs, usually below 1%, due to degradation in the gastrointestinal tract. Moreover, the epithelial lining of the gastrointestinal tract is impermeable to most polypeptides. Nasopharyngeal and passive transdermal delivery avoid the problems of enzyme degradation, but usually require penetration enhancers in order to effect systemic absorption. Even with such penetration enhancers, bioavailability will usually be very low, and the penetration enhancers can often cause undesirable irritation. In the case of nasopharyngeal administration, penetration enhancers can often damage the nasal epithelium and chronic use has been associated with hyperplasia of the nasal lining.
It is presently believed that PTH is most effectively delivered to a patient in a pulsatile fashion to achieve active bone formation. That is to say, plasma concentrations of PTH should ideally rise rapidly after administration (rapid onset) and fall rapidly after a peak has been reached (rapid decline), generally resulting in a spike in the plasma concentration profile. Thus, a particularly desirable method of administration of PTH is one that achieves such a plasma concentration profile.
For at least these reasons, it would be desirable to provide an alternative delivery method for parathyroid hormone which is patient acceptable. Any such method should avoid subcutaneous injection, limit irritation to the skin and body mucosa, and provide a desired pulsatile delivery profile as described above, among having other advantageous features. Such method should ideally provide for high levels of PTH bioavailability, be amenable to self-administration by the patient, be minimally invasive, and ideally provide a pharmacokinetic profile that is similar to, or preferably improved over, that achieved upon subcutaneous administration.